Pharmaceutical compositions and medical uses of dioxopiperidine derivatives

ABSTRACT

Phenyl-3-aminoalkyl-4-methyl-2,6-dioxopiperidines of the Formula I ##STR1## wherein: R 1  represents methoxy, ethoxy or hydroxy, 
     R 2  represents methoxy, ethoxy, hydroxy or hydrogen; 
     each R 3  independently represents methyl or ethyl; 
     R 4  represents hydrogen or methyl; 
     R 5  represents hydrogen or methyl; and 
     n represents 2 or 3, 
     and a pharmacologically acceptable acid addition salt thereof (a) have anxiolytic activity, (b) antagonize the anxiogenic activity of benzodiazepine inverse agonists, (c) reduce chronic abnormally high brain levels of serotonin or its metabolite 5-hydroxy-indoleacetic acid and (d) have antibacterial and antiviral activity. These activities are believed to be related to a reduction in serotonin turnover caused by blocking the depolarization activation of tryptophan hydroxylase. Novel compositions comprise the compounds with a benzodiazepine agonist or benzodiazepine inverse agonist.

This is a division of application Ser. No. 07/136,996, filed 12/23/87,now U.S. Pat. No. 4,835,151, which in turn is a divisional of Ser. No.06/905,525, filed Sept. 10, 1986, now U.S. Pat. No. 4,738,973.

The invention relates to the treatment of anxiety and other medicalconditions with certain3-phenyl-3-aminoalkyl-4-methyl-2,6-dioxopiperidines and to theco-administration of said compounds with benzodiazepine agonists or withbenzodiazepine inverse agonists. The invention provides pharmaceuticalcompositions containing said dioxopiperidine compounds, the use of thecompounds in the manufacture of medicaments for the treatment of anxietyor other medical conditions, and methods of treatment of anxiety orother medical conditions using the compounds.

The most widely prescribed anti-anxiety drugs are benzodiazepinesangonists and it is known that these drugs act by interacting with abenzodiazepine receptor. When used in low doses they have virtually noside effects but their anti-anxiety effectiveness is often notsufficient. Increasing the dose to a normal effective one often producesside effects such as dizziness and sedation. These doses can also leadto memory impairment. Further, tolerance to their effect usuallydevelops within four months of continuous use and there exists asubstantial risk of addiction in many patients.

The benzodiazepine agonists include benzodiazepine derivatives which canproduce 50% inhibition of tritiated flunitrazepam binding at abenzodiazepine receptor at a concentration less than 10⁻⁵ molar, andwhich produce anticonvulsant effects in animals which are subject toblockade by the benzodiazepine antagonist RO 15-1788. Prominent amongthe benzodiazepine agonists are chlorodiazepoxide (i.e.7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide), diazepam(i.e.7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one),bromazepam (i.e.7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one), prazepam(i.e.7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one),oxazepam (i.e.7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one),medazepam (i.e.7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine), lorazepam(i.e.7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one),clorazepate (i.e.7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid), flunitrazepam (i.e.5-(2-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepine-2-one), nitrazepam(1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one), and clobazam(i.e.7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione).

Specific benzodiazepine antagonists have become available which haveintrinsic pharmacological properties that are opposite to those of thebenzodiazepine agonists and which are referred to as "benzodiazepineinverse agonists". These inverse agonists enhance the performance ofanimals in learning and memory tests and it is believed that they couldbe of use in the treatment of senile dementia and Alzheimers disease.However, they are anxiogenic both in animals and man and this limitstheir usefulness.

The benzodiazepine inverse agonists include compounds which can produce50% inhibition of flunitrazepam binding at a benzodiazepine receptor ata concentration less than 10⁻⁵ molar and which produce proconvulsant orconvulsant effects in animals which are subject to blockade by thebenzodiazepine antagonist RO 15-1788. Predominant among thebenzodiazepine inverse agonists are methyl beta-carboline-3-carboxylate,ethyl beta-carboline-3-carboxylate, methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and3-methylaminocarbonyl-beta-carboline.

Benzodiazepine agonists and inverse agonists are generally believed toexert their respective anxiolytic or anxiogenic actions by respectivelyenhancing or reducing the coupling function of the benzodiazepinereceptor to the gamma-aminobutyric acid (GABA) receptor-chloride channelcomplex. It is also known that benzodiazepine agonists reduce theturnover of serotonin (5-hydroxytryptamine; 5HT) but the significance ofthis reduction has not previously been known.

It is known that the brain levels of 5HT and/or its metabolite 5-hydroxyindoleacetic acid (5HIAA) are abnormally high in certain affectivedisorders. Examples of such disorders are the Kleine-Levin syndrome(Koerber R. K. et al Neurology 1984, 34, 1597-1600),serotonin-irritation syndrome (Gianniani A. J. et al J. Clin.Psychiatry, 44, 262-4 (1983); Krueger A. P. et al, Science, 1976, 1209)and sleep apnea (Barruzzi, A. et al Sleep 3, 247-9 (1980); Mangin P. etal Adv. Biosci. 21, 217-9 (1979); Cromer, H. et al J. Neurol. Neurosurg.Psychiatry 44, 1165-7 (1981)).

It is known that 5HT activation depresses respiration (Lundberg D. B. A.et al J. Pharm. Exp. Therap. 212 397-404 (1980) and it has beensuggested that the abnormally high brain levels of 5HT are responsiblefor the disorders of the Kleine-Levin and sleep apnea syndrome andsudden infant death (Koerber R. K. et al supra). The same workers haveproposed that the 5HT excess could be controlled by the elimination oftryptophan-containing foods from the diet. Such a diet could howevercause problems because tryptophan is normally incorporated into manyessential peptides and proteins. The brain levels of 5HT also can bediminished by blocking the transformation of tryptophan into 5-hydroxytryptophan (5HTP). This can be accomplished by the use of the knowntryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) but thecontinued use of this inhibitor is precluded because of its untowardtoxic effects.

Serotonin-irritation syndrome is a condition associated with high cationenvironments, such as hot dry winds (eg. Fohn and Khansin winds),high-tension cables and waterfalls. It is believed that anions increasedegradation of 5HT and that the cations in a high cation environmentreduce this degradation by neutralizing anions and thereby increase 5HTlevels (Krueger et al supra).

Further, the strength of the immune response is known to be modulated by5HT acting via peripheral (ie. non-brain) mechanisms (Jackson J. C. etal Immunology 54, 505-512 (1985). Thus systemic administration of 5HT orits precursor 5-hydroxytryptophan (5HTP) to mice supresses the normalimmune response to an antigen challenge. Conversely, the knowntryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA)enhances the normal immune response.

It has been disclosed in GB No. 1,455,687 (also AU No. 480,855, BE No.808,958, DE No. 2,363,052.6, FR No. 7,346,904, JP No. 6,053,014 and U.S.Pat. No. 3,963,729) that inter alia3-phenyl-3-aminoalkyl-4-methyl-2,6-dioxopiperidine derivatives of thefollowing Formula I have central nervous system, especiallyantidepressant, activity: ##STR2## wherein: R₁ represents methoxy,ethoxy or hydroxy,

R₂ represents methoxy, ethoxy, hydroxy or hydrogen;

each R₃ independently represents methyl or ethyl;

R₄ represents hydrogen or methyl;

R₅ represents hydrogen or methyl; and

n represents 2 or 3.

The specific examples of compounds of Formula I stated in the U.S.Patent are3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;3-(3'-methoxyphenyl)-3-(2"-N,N-dimethylaminoethyl)-4,4-dimethyl-2,6-dioxopiperidine;3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminoethyl)-4-methyl-2,6-dioxo-piperidine;and3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminoethyl)-4,5-dimethyl-2,6-dioxo-piperidine.

It has recently been disclosed in U.S. Pat. No. 4,461,771 that compoundsof Formula I in which R₄ represents methyl and R₅ represents hydrogenreduce in vitro the activity of tryptophan hydroxylase by blocking thedepolarization-induced activation of the enzyme in the brain stem andhence are of potential use in the prophylactic treatment of thestressful disorder migrane. More recently, it has been established thatat least one compound of Formula I (viz3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;AGN 2979) also blocks in vitro the activation of tryptophan hydroxylaseresulting from exposure of brain stem slices to metabolic inhibitors ormethylxanthines or induced by incubation of supernatant preparations ofthe enzyme under phosphorylating conditions (Boadle-Biber, M. C. et alBiochem. Pharmacol. 35, 1521-6, (1986)). However, AGN 2979 has nosignificant effect in vitro upon the unactivated enzyme (Boadle-Biber,M. C. et al supra).

It has now surprisingly been found that the compounds of Formula I haveanxiolytic activity apparently without having any affinity for, orexerting any action at, the benzodiazepine receptor. The Inventorbelieves that this activity is caused by a reduction of the turnover of5HT resulting from inhibiting the activity of tryptophan hydroxylase andindicates that 5HT turnover is an important factor in the action ofanxiolytics and anxiogenics. Accordingly, the compounds are of use inthe treatment of anxiety and further in the reduction of addiction tobenzodiazepine agonists (by co-administration to gradually reducebenzodiazepine doses) and the antagonism of the anxiogenic effect ofbenzodiazepine inverse agents.

According to a first aspect of the present invention therefore, there isprovided a method of treating a patient suffering from anxiety whichcomprises administering to the patient an anti-anxiety effective amountof a compound of Formula I or a pharmaceutically acceptable saltthereof.

According to a second aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for the treatment of anxiety.

The anxiolytic activity of the compounds of Formula I can be assessed byobserving the exploratory activity of rats in the elevated plus-mazemethod of Pellow and File (Pharmacol Biochem Behav. 24, 525-529 (1986)).

As indicated above, the pharmacological mechanism for the anxiolyticactivity of the compounds of Formula I is believed to be due to theiraction in blocking the depolorisation activation of tryptophanhydroxylase resulting in a reduction in 5HT turnover. This reduction canbe measured by the method of Neff, Tozer and Brodie described by Sugrueet al (European J. Pharmacol 40, 121-30 (1976). As an illustration an ipdose of 10 mg/kg of AGN 2979 reduces the hourly turnover of 5HT in ratsby 90%. The compounds of

Formula I can be administered in various manners to achieve the desiredanxiolytic effect. The compounds can be administered alone or in theform of pharmaceutical preparations to the patient being treated eitherorally or parenterally, for example subcutaneously or intravenously. Theamount of compound administered will vary and can be any anti-anxietyeffective amount. Depending upon the patient and the mode ofadministration, the quantity of compound administered may vary over awide range to provide from about 0.1 mg/kg to 20 mg/kg*, usually 0.5mg/kg to 10 mg/kg, of body weight of the patient per dose. Unit doses ofthese compounds can contain, for example from about 10 mg to 500 mgusually 10 to 100 mg of the compound and may be administered for examplefrom 1 to 4 times daily.

The compounds of Formula I have virtually no action at benzodiazepinereceptors. The capacity of a selected number of compounds of Formula Ito displace triturated flunitrazepam from benzodiazepine receptors hasbeen measured with the results set forth in Table I below:

                  TABLE 1                                                         ______________________________________                                                  COMPOUND OF FORMULA I                                               IC.sub.50 (uM)                                                                            2979   3222   2939 3181 DIAZEPAM*                                 ______________________________________                                        [.sup.3 H] Flunitrazepam                                                                  350    1300   9000 6700 0.014                                     Binding                                                                       ______________________________________                                         *7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one      

The absence of action at benzodiazepine receptor makes the compounds ofFormula I particularly useful for co-administration with benzodiazepineagonists because the compounds appear to exert their anxiolyticactivities by different routes.

Thus, in a third aspect, the present invention provides an anxiolyticpharmaceutical composition comprising a benzodiazepine agonist and acompound of Formula I or a pharmaceutically acceptable salt thereof.

A fourth aspect of the present invention provides a pack comprising aquantity of a pharmaceutically acceptable dosage form of abenzodiazepine agonist and, separately therefrom, a quantity of acompound of Formula I or a pharmaceutically acceptable salt thereof.

A fifth aspect of the present invention provides a method for treatinganxiety in a patient which comprises administering to the patient incombination therapy a benzodiazepine agonist and a compound of Formula Ior a pharmaceutically acceptable salt thereof.

The combination therapy allows low, well tolerated, doses of thebenzodiazepine agonist to be used (with their accompanying sedativeeffect) to produce an extremely effective combined sedative andanxiolytic action better than that achieved with high doses of thebenzodiazepine alone. The combination apparently is extremely welltolerated without any distressing side effects. This aspect of theinvention has particular application to the treatment of psychoticdepressives who suffer from both anxiety and depression and haveproblems going to sleep.

The two active compounds can be administered in various manners toachieve the desired effect. They can be administered alone or in theform of pharmaceutical preparations to the patient being treated eitherorally or parenterally, for example subcutaneously or intravenously. Theamount of compound administered will vary and can be any effectiveanxiety relieving amount.

The dosage will, of course, vary according to the ratio of combinationof benzodiazepine agonist and compound of Formula I employed, mode ofadministration, patient and therapy desired. In general a suitable dailydose of the dioxopiperidine derivatives of Formula I is from 50 to 700mg, preferably 150 to 500 mg. The potencies of the benzodiazepineagonists vary and therefore an indicated weight ratio of dioxopiperidineto benzodiazepine can be from 400:1 to 4:1. Conveniently, however, thedose of the benzodiazepine is from about 5 to 50% of the daily dose forthe anxiety indication.

The daily dosage may be conveniently administered 2 to 4 times a day individed doses or once or twice a day in sustained release form. Thebenzodiazepine agonist and dioxopiperidine may be combined in a singledosage form or retained separately until required for concomitantadministration.

The absence of action at benzodiazepine receptors also makes thecompounds of Formula I particularly useful for co-administration withbenzodiazepine inverse agonists to antagonize the anxiogenic activitythereof and hence extend their usefulness to treat senile dementia andAlzheimer's disease.

Thus, in a sixth aspect, the invention provides a pharmaceuticalcomposition comprising a benzodiazepine inverse agonist and a compoundof Formula I or a pharmaceutically acceptable salt thereof.

A seventh aspect of the invention provides a pack comprising a quantityof a pharmaceutically acceptable dosage form of a benzodiazepine inverseagonist and, separately therefrom, a quantity of a pharmaceuticallyacceptable dosage form of a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

A eighth aspect of the present invention provides a method for treatingsenile dementia or Alzheimer's disease in a patient which comprisesadministering to the patient in combination therapy a benzodiazepineinverse agonist and a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

The two active compounds can be administered in various manners toachieve the desired effect. They can be administered alone or in theform of pharmaceutical preparations to the patient being treated eitherorally or parenterally, for example subcutaneously or intravenously.

The dosage will, of course, vary according to the ratio of combinationof benzodiazepine inverse agonist and compound of Formula I employed,mode of administration, patient and therapy desired. In general asuitable daily dose of the dioxopiperidine derivatives of Formula I isfrom 50 to 700 mg, preferably 150 to 500 mg. The potencies of thebenzodiazepine inverse agonists vary and therefore an indicated weightratio of dioxopiperidine to benzodiazepine inverse agonist can be from200:1 to 4:1.

The daily dosage may be conveniently administered 2 to 4 times a day individed doses or once or twice a day in sustained release form. Thebenzodiazepine inverse agonist and dioxopiperidine may be combined in asingle dosage form or retained separately until required for concomitantadministration.

It also has unexpectedly been found that the compounds of Formula I candiminish the brain levels of 5HT and 5HIAA under normal conditions andare of use in the treatment of disorders associated with abnormally highlevels of 5HT in the brain such as Kleine-Levin, sleep apnea,serotonin-irritation, and sudden infant death syndromes.

Thus, according to a ninth aspect of the present invention, there isprovided a method of treating a patient having a chronic abnormally highbrain level of 5HT or 5HIAA which comprises administering to the patientan effective 5HT- or 5HIAA- lowering amount of a compound of Formula Ior a pharmaceutically acceptable salt thereof. Said amount usually willbe in the range 0.1 mg/kg to 20 mg/kg, especially 0.5 to 10 mg/kg.

A tenth aspect of the present invention provides the use of a compoundof Formula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the reduction of chronic abnormally highbrain levels of 5HT or 5HIAA.

The compounds of Formula I can be administered in various manners toachieve the desired effect. The compounds can be administered alone orin the form of pharmaceutical preparations to the patient being treatedeither orally or parenterally, for example subcutaneously orintravenously. The amount of compound administered will vary and can beany effective amount. Depending upon the patient and the mode ofadministration, the quantity of compound administered may vary over awide range to provide from about 0.1 mg/kg to 20 mg/kg, usually 0.5mg/kg to 10 mg/kg, of body weight of the patient per dose. Unit doses ofthese compounds can contain, for example from about 10 mg to 500 mgusually 10 to 100 mg of the compound and may be administered for examplefrom 1 to 4 times daily.

It is believed that the compounds of Formula I lower the brain andperipheral levels of 5HT and its metabolite 5HIAA and hence relievedisorders associated with chronic abnormally high levels of 5HT or 5HIAAin the brain. Accordingly, the compounds of Formula I and theirpharmacologically acceptable acid addition salts are useful in thetreatment of disorders associated with abnormally high brain levels of5HT and/or 5HIAA.

The activity of the compounds to lower brain 5HT or 5HIAA levels can beassessed by measuring the concentrations of 5HIAA in homogenates ofwhole brains in 0.4M perchloric acid from animals treated with thecompounds following the method described by J. Wagner et al J.Neurochem., 38 1241 (1982) and comparing the results with those obtainedfrom animals treated with saline. As an illustration the whole brainlevel of 5HIAA was reduced by 20% 4.5 hours after treating mice with anip dose of 10 mg/kg of d,13-(3-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidinehydrochloride.

It has further unexpectedly been found that the compounds of Formula Ienhance the immune response in mice by a mechanism which probablyinvolves a decreased synthesis of 5HT in the periphery. Hence, thecompounds of Formula I are of potential use in combatting bacterial andviral infections in animals and in man.

Thus, according to an eleventh aspect of the present invention, there isprovided a method of treating a patient having a bacterial or viralinfection which comprises administering to the patient an effective 5HT-or 5HIAA- lowering amount of compound of Formula I or a pharmaceuticallyacceptable salt thereof. Said amount usually will be in the range 0.1mg/k to 20 mg/kg, especially 0.5 to 10 mg/kg.

According to a twelth aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for the treatment of bacterial or viralinfections in a patient.

The compounds of Formula I can be administered in various manners toachieve the desired antibacterial or antiviral effect. The compounds canbe administered alone or in the form of pharmaceutical preparations tothe patient being treated either orally or parenterally, for examplesubcutaneously or intravenously. The amount of compound administeredwill vary and can be any effective amount. Depending upon the patientand the mode of administration, the quantity of compound administeredmay vary over a wide range to provide from about 0.1 mg/kg to 20 mg/kg,usually 0.5 mg/kg to 10 mg/kg, of body weight of the patient per dose.Unit doses of these compounds can contain, for example from about 10 mgto 500 mg usually 10 to 100 mg of the compound and may be administeredfor example from 1 to 4 times daily.

The activity of the compounds to potentiate the immunoresponse can bedetermined by measuring, by the method described by Elliott and Rozmann,(J. Immunol. 115, 495 (1975), the number of immunoglobin M and G (IgMand IgG) antibody forming spleen cells from mice 3-7 days afterimmunisation with 5×10⁸ sheep red blood cells, the mice having beenpretreated with three daily doses of the compounds. As an illustrationthe number of IgM antibody forming spleen cells from mice treated withthree daily doses of3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidinehydrochloride 10 mg/kg ip was 1128×10⁶ on day 4 after immunization whichwas 189% above control values.

The compounds of general Formula I have the phenyl moiety substituted inone or both meta positions by methoxy, ethoxy or hydroxy. It ispresently preferred that the substituent(s) should be hydroxy or,especially, methoxy. It is also preferred that there should be only onesubstituent and that when there are two substituents they should be thesame.

The amino group of the compounds of Formula I is dimethylamino,diethylamino or methylethylamino with dimethylamino being presentlypreferred. The amino group is connected to the piperidine ring by adivalent ethylene (i.e. n=2) or trimethylene (i.e. n=3) radical withtrimethylene being presently preferred.

The piperidine ring of the compounds of Formula I is substituted in the4-position with methyl and optionally by one or two further methylgroups in the 4 and/or 5 positions. It is presently preferred that thereis one further methyl group in the 4 or 5 position, especially in the4-position.

Examples of compounds of Formula I include the following:

3-(3'-methoxyphenyl)-3-(2"-N,N-dimethylaminoethyl)-4,4-dimethyl-2,6-dioxopiperidine

3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine(compound 2979--see later);

3-(3'-methoxyphenyl)-3-(2"-N,N-diethylaminoethyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3'-methoxyphenyl)-3-(3"-N,N-diethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3'-hydroxyphenyl)-3-(2"-N,N-dimethylaminoethyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3'-hydroxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3'-methoxyphenyl)-3-(2"-N,N-dimethylaminoethyl)-4,5-dimethyl-2,6-dioxopiperidine(compound 2939--see later);

3-(3'-methoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,5-dimethyl-2,6-dioxopiperidine(compound 3181--see later);

3-(3'-ethoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3'-ethoxyphenyl)-3-(3"-N,N-diethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3',5'-dimethoxyphenyl)-3-(3"-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine(compound 3222--see later);

3-(3',5'-dimethoxy)-3-(2"-N,N-dimethylaminoethyl)-4,4-dimethyl-2,6-dioxopiperidine;

3-(3',5'-dimethoxy)-3-(3"-N,N-dimethylaminopropyl)-4,5-dimethyl-2,6-dioxopiperidine;and

3-(3',5'-dimethoxy)-3-(2"-N,N-dimethylaminoethyl)-4,5-dimethyl-2,6-dioxopiperidine;

The above compounds may be administered in free base form, as an alkalimetal or alkaline earth metal salt or as a pharmaceutically acceptableacid addition salt with the proviso that an alkali metal or alkalineearth metal salt is not normally combined with an acid addition saltexcept in a layer formulation. Representative acid addition salt formsinclude organic acid salt forms such as the maleate and methanesulphonate and mineral acid salt forms such as the hydrochloride andperchlorate.

The pharmaceutical formulations in which form the active compounds ofthe invention will normally be utilized are prepared in a manner wellknown per se in the pharmaceutical art and usually comprise at least oneactive compound of Formula I in admixture or otherwise in associationwith a pharmaceutically acceptable carrier or diluent therefor. Formaking those formulations the active ingredient will usually be mixedwith a carrier, or diluted by a diluent, or enclosed or encapsulated ina capsule, sachet, cachet, paper or other container. A carrier ordiluent may be solid, semi-solid or liquid material which serves as avehicle, excipient or medium for the active ingredient. Suitablecarriers or diluents are well known per se.

The formulations may be adapted for enteral or parenteral use and may beadministered to the patient in the form of tablets, capsules, dragees,suppositories, syrups, suspensions or the like.

Preferably the compounds of Formula I, and any benzodiazepine agonist orinverse agonist for co-administration therewith, are administered orallyin the form of a unit dosage. For co-administration, such as a unitdosage may, if desired, have said active agents separately encompassedtherein e.g. in separate layers in a layer tablet. Suitably, each unitdose of compound of Formula I is in the range 25 to 200 mg and each unitdose of benzodiazepine agonist or inverse agonist is in the range of0.05 to 50 mg.

The term "unit dosage form" is used herein to mean a single or multipledose form containing a quantity of the active ingredient in admixturewith or otherwise in association with the diluent or carrier, saidquantity being such that one or more predetermined units are normallyrequired for a single therapeutic administration. In the case ofmultiple dose forms such as liquids or scored tablets, saidpredetermined unit will be one fraction, such as a 5 ml (teaspoon)quantity of a liquid or a half or quarter of a scored tablet, of themultiple dose form.

Aside from the active agents the compositions may containpharmaceutically inert organic or inorganic adjuvants, optionallygranulating agents, binding agents lubricants, dispersing agents,wetting agents and preservatives. Moreover, the pharmaceuticalcompositions may contain colouring, flavouring and sweenteningsubstances. Adjuvants for the production of tablets may be e.g. calciumcarbonate, lactose micro-crystalline cellulose, mannitol or talc. Starchand alginic acid or micro-crystalline cellulose may be used asgranulating and disintegrating agents, starch, polyvinylpyrrolidone andgelatine may be used as binding agents and magnesium stearate, stearicacid, colloidal silica and talc as lubricants. Tablet formulation may becoated or uncoated, the coating having the purpose of delaying thedisintegration and absorption in the gastrointestinal tract. Suitablesuspending agents for the production of liquid administration forms aree.g. methyl cellulose and sodium alginate. Capsule formulation maycontain the active agents on their own or together with an inert soliddiluent e.g. calcium phosphate, corn starch, lactose, or mannitol.

The invention is illustrated in the following non-limiting Examples.

EXAMPLE 1

Tablets each having the following composition were prepared byconventional techniques:

    ______________________________________                                                           mg/tablet                                                  ______________________________________                                        (a)    Compound AGN 2979 base                                                                          50                                                   (b)    Lactose           51.5                                                 (c)    Maize starch dried                                                                              45                                                   (d)    magnesium stearate                                                                              1.5                                                  ______________________________________                                    

EXAMPLE 2

    ______________________________________                                                             mg/suppository                                           ______________________________________                                        (a)    Compound AGN 2979 HCl                                                                             20                                                 (b)    Oil of Theobroma (cocoa butter)                                                                   980                                                ______________________________________                                    

The compound (a) is powdered and passed through a BS No. 100 sieve andtriturated with molten oil of Theobroma at 45° C. to form a smoothsuspension. The mixture is well stirred and poured into moulds each ofnominal 1 G capacity to produce suppositories.

EXAMPLE 3 Tablet Formulation

    ______________________________________                                        (a)    Compound AGN 2979 base                                                                              100    g                                         (b)    Tranxene              10     g                                         (c)    Wheat starch          7      g                                         (d)    Lactose               20     g                                         (e)    Magnesium Stearate    1      g                                         ______________________________________                                    

The mixture is compressed into 1000 tablets each weighing 138 mg.Analogously an equal weight of Compound AGN 2939 or 50 g of Compound AGN3222 can be substituted for Compound AGN 2979.

EXAMPLE 4 Pill Formulation

    ______________________________________                                                               per pill                                               ______________________________________                                        (a)     Compound AGN 2979 HCl                                                                              50    mg                                         (b)     Diazepam             3     mg                                         (c)     Corn starch          45    mg                                         (d)     Liquid glucose       7     ml                                         ______________________________________                                    

The pills are prepared by blending the active ingredients (a) and (b)and the corn starch, then adding the liquid glucose with thoroughkneading to form a plastic mass from which the pills are cut and formed.

EXAMPLE 5 Gelatine Capsule Formulation

    ______________________________________                                                              per capsule                                             ______________________________________                                        (a)    Compound AGN 2979 HCl                                                                              50     mg                                         (b)    Chlorodiazepoxide HCl                                                                              2.5    mg                                         (c)    Talc                 20     mg                                         ______________________________________                                    

A capsule is prepared by passing dry powdered active ingredients (a) and(b) and powdered talc in the above proportions through a fine meshscreen and mixing them well. The powder is then filled into hard gelatincapsules at a net fill of 72.5 mg per capsule.

EXAMPLE 6 Suppository

    ______________________________________                                                             mg/suppository                                           ______________________________________                                        (a)    Compound 2979 HCl   20                                                 (b)    Diazepam            1                                                  (c)    Oil of Theobroma (cocoa butter)                                                                   979                                                ______________________________________                                    

The compound (a) is powdered and passed through a BS No. 100 sieve andtriturated with molten oil of Theobroma at 45° C. to form a smoothsuspension. The mixture is well stirred and poured into moulds each ofnominal 1 G capacity to produce suppositories.

EXAMPLE 7

This Example illustrates the anxiolytic activity of compounds of FormulaI.

Fifty seven male hooded Lister rats (Olac Ltd., Bicester) were testedfor exploratory activity in the elevated plus-maze test of Pellow andFile (Pharmacol Biochem Behav., 24, 525-529 (1986)). The rats wererandomly assigned to a control group (11 rats) or test groups to beinjected with 3 mg/kg AGN 2979 (7 rats), 10 mg/kg AGN 2979 (8 rats), 30mg/kg (8 rats); 60 mg/kg (8 rats), 80 mg/kg (7 rats) or 100 mg/kg (8rats). Each rat was injected intraperitoneally 30 minutes before testingand the rats were tested in randomised order between 1400 and 1600 h.

Each rat was placed in the central square of the elevated plus-maze andobserved by an observer blind to the drug treatment. The number ofentries into the open and closed arms and the time spent in each type ofarm was recorded. The plus-maze was a cruciform structure having opposedopen arms (50×10 cm) and opposed enclosed arms (50×10×40) with openroofs. Overall, AGN 2979 caused a significant elevation in percentagenumber of open arm entries (F(5,50)=3.51, p 0.01); a significantreduction in the total number of arm entries (F(6,50)=6.3, p 0.0001);but no significant effect in percentage time spent on the open arms(F(6,50)=2.1, p 0.07). The mean percentage number of open arm entries,mean percentage time spent on the open arms, and the mean total numberof arm entries are given in Table II below together with the respectivestandard deviations.

                  TABLE II                                                        ______________________________________                                        Dose  % open arm entry                                                                             % open arm time                                                                           total entries                                ______________________________________                                        0     37.5 ± 10.2 16.4 ± 12.9                                                                            11.1 ± 5.4                                3     34.8 ± 12.7 17.0 ± 12.2                                                                            13.3 ± 5.3                                10    28.8 ± 7.8  16.6 ± 7.6                                                                             13.9 ± 5.1                                30    25.3 ± 11.3 13.8 ± 11.0                                                                            10.8 ± 3.3                                60    30.9 ± 16.6 6.4 ± 5.8                                                                               6.4 ± 4.6                                80    38.1 ± 10.5 8.6 ± 6.7                                                                               5.9 ± 2.8                                100   48.8 ± 11.0 6.3 ± 3.4                                                                               5.9 ± 1.4                                ______________________________________                                    

The results indicate that AGN 2979 is anxiolytic at least at an initialsingle ip dose of 100 mg/kg and sedative at initial single ip doses of60, 80 and 100 mg/kg. However, it is expected that in a chronic testinganxiolytic activity will be apparent at doses below 100 mg/kg and thatthe sedative action will cease.

The anxiolytic activity observed is between that previously obtained forchlorodiazepoxide and diazepam and at least as good as that obtained forthe pyrazolopyridazine derivative tracazolate and the triazolopyridineCL 218,872 (see Pellow and File, Pharmacol Biochem Behav., 24, 525-529)(1986)).

The sedative effect of AGN 2979 was tested using the Holeboard test(File and Ward: 11, Psychopharmacologia 44, 53-59 (1975)). Forty eightmale hooded Lister rats (Olac. Ltd., Bicester) were randomly assigned toa control group (10 rats) or to test groups to be injected with 3 mg/kgAGN 2979 (9 rats); 10 mg/kg (10 rats); 30 mg/kg (9 rats) or 100 mg/kg (9rats). Each rat was injected intra-peritoneally 30 minutes beforetesting and the rats were tested in randomised order between 0800 and1200 h.

Each rat was placed in the centre of the Holeboard and its behaviorautomatically recorded by infra-red beam breaks 5 minutes. Overall, AGN2979 significantly reduced motor activity (F(4,42)=7.3, p 0.001) and thenumber of head dips (F(4,43)=2.8, p 0.05). There was no significantdecrease in the number of rears made (F(4,43)=2.15, p=0.09) or timespent head dipping (F(4,43)=2.4, p=0.06). The mean values and standardderivations (SD) are given in Table III below.

                  TABLE III                                                       ______________________________________                                        Dose mg/kg  0       3       10    30    100                                   ______________________________________                                        Motor Activity*                                                                           334.9   351.2   330.9 279.8 224.3                                 (SD)        (54.9)  (69.3)  (49.8)                                                                              (70.8)                                                                              (58.4)                                Number of Rears                                                                           72.5    67.2    68.8  64.0  57.0                                  (SD)        (9.3)   (9.8)   (10.6)                                                                              (15.8)                                                                              (14.7)                                Number of Head-                                                                           34.6    31.7    34.4  27.5  22.2                                  dips (SD)   (7.2)   (7.7)   (9.9) (14.3)                                                                              (6.5)                                 Time Head Dipping                                                                         31.4    31.3    39.7  28.2  21.9                                  (secs) (SD) (10.5)  (9.7)   (13.3)                                                                              19.3  6.3                                   ______________________________________                                         *Number of beam breaks                                                   

These results indicate that AGN 2979 is sedative at least at an initialsingle ip dose of 100 mg/kg. However, the sedative effect is modestcompared with that of benzodiazepines. As mentioned above, it isexpected that the sedative effect will cease on chronic administrationof AGN 2979.

EXAMPLE 8

As an illustrative example showing the efficacy of the combination ofthe benzodiazepine and a compound of Formula I six hospitaliseddepressive patients treated with the di-potassium salt of clorazepate(Trade Mark Tranxene) (50 mg/day) and an ineffective amount of CompoundAGN 2979 (30-150 mg/day) showed no significant reduction in Hamiltonanxiety score during 14-28 days. However, eight hospitalised depressivesgiven Tranxene (50 mg/day) together with Compound AGN 2979(200-400mg/day) had their Hamilton anxiety scores reduced from a mean of 35 to amean of 6 (84% reduction) during 21-28 days.

EXAMPLE 9

This example illustrates the use of compounds of Formula I in thetreatment of sleep apnea. A male subject aged 54 years, height 178 cmand weighing 83 kilograms having persistent awakening episodes ofobstructive sleep apnea has been treated with compound AGN 2979 at adaily dose level of 120 mg. Sleep apnea episodes at first decreased inintensity and completely disappeared after one week of treatment. Thepatient has since remained symptom free for 14 months on a singlemaintenance dose of 120 mg every four days.

In the Examples above, the active compound was used in the form of theracemate (d,1). However, as is apparent from Formula I herein, AGN 2979and other compounds of said formula exist as optical isomers.Experimental work to date indicates that the individual isomers are ofsubstantially equal activity in the medical uses to which thisapplication relates.

I claim:
 1. A method of antagonizing the anxiogenic effect of a benzodiazepine inverse agonist comprising administering to a patient being treated with a benzodiazepine inverse agonist, an anxiolytic amount of Formula I ##STR3## wherein: R₁ represents methoxy, ethoxy or hydroxy,R₂ represents methoxy, ethoxy, hydroxy or hydrogen; each R₃ independently represents methyl or ethyl; R₄ represents hydrogen or methyl; R₅ represents hydrogen or methyl; and n represents 2 or 3,or a pharmacologically acceptable acid addition salt thereof.
 2. A method of reducing chronic abnormally high brain levels of serotonin (5HT) or 5-hydroxy-indoleacetic acid (5HlAA), which comprises administering to a patient having a chronic abnormally high brain level of 5HT or 5HlAA, an effective 5HT- or 5HlAA-lowering amount of a compound of Formula I ##STR4## wherein: R₁ represents methoxy, ethoxy or hydroxy,R₂ represents methoxy, ethoxy, hydroxy or hydrogen; each R₃ independently represents methyl or ethyl; R₄ represents hydrogen or methyl; R₅ represents hydrogen or methyl; and n represents 2 or 3,or a pharmacologically acceptable acid addition salt thereof.
 3. The method of claim 1 in which R₁ represents methoxy or hydroxy, R₂ represents hydrogen, each R₃ represents methyl and n is
 3. 4. The method of claim 1, in which R₄ represents methyl and R₅ represents hydrogen.
 5. The method of claim 1 in which the dioxopiperidine is 3-(3'-methoxyphenyl)-3-(3"-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine.
 6. The method of claim 2 in which R₁ represents methoxy or hydroxy, R₂ represents hydrogen, each R₃ represents methyl and n is
 3. 7. The method of claim 2, in which R₄ represents methyl and R₅ represents hydrogen.
 8. The method of claim 2 in which the dioxopiperidine is 3-(3'-methoxyphenyl)-3-(3"-dimethylaminopropyl)-4,4-dimethyl-2,6-dioxopiperidine. 